Impact of Chain Length on Antibacterial Activity and Hemocompatibility of Quaternary N‑Alkyl and N,N‑Dialkyl Chitosan Derivatives

• Published in: Biomacromolecules Vol. 16; no. 5; pp. 1449 - 1460
• Main Authors: Sahariah, Priyanka, Benediktssdóttir, Berglind E, Hjálmarsdóttir, Martha Á, Sigurjonsson, Olafur E, Sørensen, Kasper K, Thygesen, Mikkel B, Jensen, Knud J, Másson, Már
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 11-05-2015
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Biopolymers - chemistry; Biopolymers - pharmacology; Caco-2 Cells; Chitosan - analogs & derivatives; Chitosan - chemical synthesis; Chitosan - chemistry; Chitosan - pharmacology; Erythrocytes - drug effects; Escherichia coli; Escherichia coli - drug effects; Humans; Microbial Sensitivity Tests; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Spectroscopy, Fourier Transform Infrared; Staphylococcus aureus; Staphylococcus aureus - drug effects; Structure-Activity Relationship
• ISSN: 1525-7797; 1526-4602
• DOI: 10.1021/acs.biomac.5b00163

A highly efficient method for chemical modification of chitosan biopolymers by reductive amination to yield N,N-dialkyl chitosan derivatives was developed. The use of 3,6-O-di-tert-butyldimethylsilylchitosan as a precursor enabled the first 100% disubstitution of the amino groups with long alkyl chains. The corresponding mono N-alkyl derivatives were also synthesized, and all the alkyl compounds were then quaternized using an optimized procedure. These well-defined derivatives were studied for antibacterial activity against Gram positive S. aureus, E. faecalis, and Gram negative E. coli, P. aeruginosa, which could be correlated to the length of the alkyl chain, but the order was dependent on the bacterial strain. Toxicity against human red blood cells and human epithelial Caco-2 cells was found to be proportional to the length of the alkyl chain. The most active chitosan derivatives were found to be more selective for killing bacteria than the quaternary ammonium disinfectants cetylpyridinium chloride and benzalkonium chloride, as well as the antimicrobial peptides melittin and LL-37.